Pregnancy and the postpartum period have been associated with increased risk of HIV-1. In Africa, where both HIV-1 seroprevalence and fertility rates are high, the pregnancy/postpartum period may be one in which HIV-1 acquisition contributes substantially to HIV-1 in women. Pregnancy, delivery, and the postpartum period are associated with hormonal, genital mucosal, and genital flora changes that could predispose to acquisition of HIV-1. Project 1 will enroll 2,000 HIV-1 uninfected women identified during pregnancy and followed to 9 months postpartum to determine risk and cofactors of HIV-1 incidence. Women who acquire HIV-1 will be compared to women who do not in order to determine the role of genital coinfections, ulcers, delivery practice, lactation, partner characteristics, vaginal flora changes, HSV-2, genital innate immune factors, and systemic immune activation on HIV-1 transmission. In addition, changes in cofactors over the course of pregnancy and postpartum may influence susceptibility to HIV-1. Thus, in a subset of 100 women we will compare genital innate immune factors, and systemic cellular immune activation longitudinally during pregnancy, early postpartum, and later postpartum. These comparisons will provide opportunity to determine patterns of change in the genital tract during this dynamic period of change in women. In quantifying co-infections, mucosal innate immune responses, and systemic cellular immune activation, we will be able to determine interactions between these important determinants in 3 different but inter-related areas (co-infection, mucosal innate milieu, systemic cellular) that affect susceptibility to HIV-1. Project 1 will have scientific links to Project 2 (effects of changes in vaginal flora on HIV-1 transmission), Project 3 (which will involve cytokine profile analyses within women from the Project 1 cohort) and Project 4 (adaptive humoral mucosal responses in HIV-1 uninfected women with HIV-1 infected partners). Because of the complexity of the female genital ecosystem and the variety of factors that could alter susceptibility to HIV-1, each Project will focus on complementary factors that may modify transmission of HIV-1. Together, these will lead to a multi-faceted evaluation of transmission in women in different important groups of women at risk for HIV-1, (pregnant/postpartum, female sex workers, and discordant couples), that conceivably share some cofactors for HIV-1 susceptibility but are distinct in others.